US4500451A - New protein PP13 extracted from human placental tissues and use thereof - Google Patents

New protein PP13 extracted from human placental tissues and use thereof Download PDF

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Publication number
US4500451A
US4500451A US06/524,201 US52420183A US4500451A US 4500451 A US4500451 A US 4500451A US 52420183 A US52420183 A US 52420183A US 4500451 A US4500451 A US 4500451A
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Prior art keywords
protein
proteins
substrate
extracted
human
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Hans Bohn
Walter Kraus
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Siemens Healthcare Diagnostics GmbH Germany
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Behringwerke AG
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Assigned to BEHRINGWERKE AKTIENGESELLSCHAFT, A CORP. OF GERMANY reassignment BEHRINGWERKE AKTIENGESELLSCHAFT, A CORP. OF GERMANY ASSIGNMENT OF ASSIGNORS INTEREST. Assignors: BOHN, HANS, KRAUS, WALTER
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/46—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
    • C07K14/47—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
    • C07K14/4701—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals not used
    • C07K14/4715—Pregnancy proteins, e.g. placenta proteins, alpha-feto-protein, pregnancy specific beta glycoprotein
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
    • G01N33/689—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids related to pregnancy or the gonads
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10S530/00—Chemistry: natural resins or derivatives; peptides or proteins; lignins or reaction products thereof
    • Y10S530/827—Proteins from mammals or birds
    • Y10S530/85—Reproductive organs or embryos
    • Y10S530/851—Placenta; amniotic fluid

Definitions

  • the invention relates to a new protein (PP 13 ), a process for enriching and isolating it from an extract of human placentae and its use.
  • the present invention describes the isolation and characterization of a new soluble protein which is called PP 13 .
  • the invention relates to the protein PP 13 which is characterized by (a) an electrophoretic mobility in the same range as albumin,
  • the aminoacid composition of PP 13 is shown in the table below:
  • tissue protein In order to illustrate the characterizing features of the tissue protein, the following may be said:
  • the isoelectric point was determined with a column (440 ml) supplied by LKB, Sweden.
  • the so-called Ampholine.sup.(R) mixture had a pH range of 4.0 to 6.0.
  • the sedimentation coefficient was determined in an analytical ultracentrifuge supplied by Beckman (Spinco apparatus, model E) at 60,000 rpm in double-sector cells using the UV scanner technique at 280 nm.
  • the solvent used was a 0.05 M phosphate buffer (pH 6.8) which contained 0.2 mole/liter of NaCl.
  • the protein concentration was adjusted to an optical density (O.D.) of about 3.
  • the calculated sedimentation coefficient was based on water at 20° C.
  • the sedimentation equilibrium method was employed. The concentration of the protein in this was adjusted to about 1.0 0.D.. The determination was carried out at 9,000 rpm. The recording was carried out using UV optics at 280 nm employing a photoelectric scanner.
  • a 7.5% (g/100 ml) polyacrylamide (PAA) gel which contained 0.1% (g/100 ml) of sodium dodecyl sulfate (SDS) was used.
  • the comparison substances used were human placental lactogen (HPL) and human albumin and its aggregates.
  • the substance was dissolved at a concentration of 0.10% (g/100 ml) in distilled water.
  • the analysis of the carbohydrates was carried out as follows: after hydrolysis of the glycosidic bonds, the liberated neutral sugars were separated as borate complexes on an anion exchange column (Y.C. Lee et al., Anal. Biochem. 27, 567 (1969)), underwant a color reaction in the eluate by adding Cu(I) bicinchoninate reagent (K. Mopper and M. Gindler, Anal. Biochem. 56, 440 (1973)), and were quantitatively determined using rhamnose as an internal standard. The amino sugars were detected and determined by their reaction with ninhydrin. The content of neuraminic acid was found by the method of Warren (Methods in Enzymology, Vol. VI, 463-465 (1963)).
  • the aminoacid analysis was carried out by the method of S. Moore, D. H. Spackman, W. H. Stein, Anal. Chem. 30, page 1185 (1958) using the Multichrome B liquid chromatograph supplied by Beckman. 1/2 cystine was determined as cysteic acid after oxidation of the proteins with performic acid (S. Moore et al., Anal. Chem. 30, page 1185 (1958)) and subsequent chromatography (S. Moore, J. Biol. Chem., 238, page 235 (1963)). The content of tryptophane was found by direct photometric determination by the method of H. Edelhoch, Biochemistry 6, page 1948 (1967).
  • PP 13 has the following properties which can be used in a process for its isolation by employing methods appropriate for these properties:
  • acridine bases for example 2-ethoxy-6,9-diaminoacridine lactate (Rivanol.sup.(R)) at pH values between 4 and 9 and at a concentration of base of 0.2 to 0.8% (g/100 ml).
  • the invention also relates to a process for isolating PP 13 which comprises fractioning an extract of human placentae using the above properties.
  • PP 13 can be isolated by appropriate combination of the methods mentioned which bring about an enrichment of PP 13 or separation of this protein from other proteins.
  • the present invention is to be seen as relating to the individual steps for the enrichment of PP 13 and to process for the purification of PP 13 resulting from a combination of the methods for enrichment.
  • the extract from human placentae can be employed directly for immunoadsorption.
  • concentration of PP 13 in the placental extract is relatively low, it is advantageous, by preliminary fractionation of the extract, first specifically to enrich the protein PP 13 using methods which are suitable for the fractionation of proteins on a relatively large scale; for example by fractional precipitation with neutral salts or organic cations, by gel filtration or by ion exchange chromatography.
  • immunochemical methods can also be used, since PP 13 has antigenic properties. Specific antibodies are formed on immunizing animals with this protein.
  • An antiserum which can be used for this purpose can be obtained as follows: a polyvalent antiserum is obtained by immunizing rabbits with a placental protein fraction containing PP 13 (for example a mother liquor from the crystallization of human placental lactogen (HPL) by the method of Bohn H., Experientia 27 (1971) 1223), and this antiserum contains, inter alia, antibodies against PP 13 .
  • This antiserum can be made highly specific for the antigen PP 13 by absorption with normal human serum and those placental fractions which do not contain PP 13 , or with purified placental proteins (for example HPL, PP 11 , PP 12 and PP 16 ).
  • this antiserum can be used for the immunologic determination of PP 13 and, on the other hand, for the preparation of an immunoabsorbent which can be employed for enriching and isolating PP 13 .
  • Monospecific antisera can be prepared by immunizing animals by known methods using the purified PP 13 obtained by the method in the present Application.
  • FIG. 1a shows the immunologic reaction of PP 13 with a specific rabbit antiserum after separation in an electric field on agar-containing gel.
  • FIG. 1b shows the separation of the proteins in the serum rendered visible by their immune reaction with a rabbit antiserum against human serum (HS).
  • the Ouchterlony gel diffusion technique can also be used for the immunologic detection of PP 13 (cf. Schultze and Heremans, Molecular Biology of Human Proteins, vol. 1 page 134) or, if necessary, more sensitive methods, such as radioimmunoassays or enzyme immunoassays.
  • PP 13 is a protein which is "specific" to the placenta. Proteins of this type are generally found in increasing amounts in the serum as pregnancy advances; thus they can be used as parameters for monitoring pregnancy. On the other hand, placenta-specific proteins can frequently also be detected in the serum of patients with tumors, particularly with trophoblastic and embryonal tumors, or are localized in the tissue of the tumors; thus they can be used in diseases of this type as markers for monitoring the progress of the disease and for monitoring therapy.
  • PP 13 can be used to prepare antisera which can be used to detect and determine PP 13 .
  • 1,000 kg of deep-frozen human placentae were reduced in size in a cutting mixer and extracted with 1,000 liters of a 0.4% strength (g/100 ml) saline solution.
  • the extract was adjusted to pH 6.0 with 20% strength (g/100 ml) acetic acid, and 200 liters of a 3% strength (g/100 ml) solution of 2-ethoxy-6,9-diaminoacridine lactate (Rivanol(R), Hoechst AG) were added, with stirring.
  • the precipitate was removed by centrifugation, 500 liters of a 2.5% strength (g/100 ml) NaCl solution were added and the mixture was stirred for 4 hours.
  • fraction A 1,200 g of fraction A were dissolved in water and dialyzed against a 0.01 M tris-HCL buffer (pH 8.0) which contained 0.05% (g/100 ml) of NaN 3 (buffer solution I). The remaining solution was applied to a column (60 ⁇ 65 cm) filled with Sephadex G-150 and eluted with buffer solution I. The eluates containing the low molecular weight proteins (MW 10,000-40,000) were combined and are denoted fraction B.
  • fraction B The proteins in fraction B were adsorbed on DEAE cellulose (column 10 ⁇ 28 cm). The column was then washed with buffer solution I and eluted with 5% (g/100 ml) saline solution. The eluate was reduced in volume by ultrafiltration and dialyzed against a 0.1 M tris-HCl buffer of pH 8 which contained 1 mole/liter of NaCl and 0.1% sodium azide (buffer solution II) (fraction C).
  • the immunoadsorbent was suspended in buffer solution II, introduced into a chromatography column (5.5 ⁇ 22 cm) and washed with buffer solution II. Then fraction C was applied to the column, the PP 13 being bound by immunoadsorption. The column was then thoroughly washed with buffer II; the adsorbed protein was then eluted from the column using about 600 ml of 3 M potassium thiocyanate solution. The eluates containing PP 13 were dialyzed against buffer solution II and reduced in volume to about 20 ml by ultrafiltration. The yield per adsorption was about 10 mg of PP 13 . Immediately after the elution of PP 13 , the adsorbent in the column was neutralized again with buffer solution II and thoroughly washed; it was then used again for binding PP 13 by immunoadsorption.
  • the protein obtained by immunoadsorption was frequently contaminated with non-specifically bound serum proteins and other placental tissue proteins.
  • the removal of the major part of the accompanying serum proteins was achieved by gel filtration on Sephadex G-100.
  • the remaining accompanying proteins were then removed by inverse or negative immunoadsorption, that is to say using carrier-bond antibodies against the proteins still present as impurities (HPL, PP 12 , PP 16 and serum proteins.)

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Molecular Biology (AREA)
  • Immunology (AREA)
  • Biochemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Medicinal Chemistry (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Biomedical Technology (AREA)
  • Hematology (AREA)
  • Pregnancy & Childbirth (AREA)
  • Reproductive Health (AREA)
  • Genetics & Genomics (AREA)
  • Biophysics (AREA)
  • Gynecology & Obstetrics (AREA)
  • Urology & Nephrology (AREA)
  • Food Science & Technology (AREA)
  • Pathology (AREA)
  • Cell Biology (AREA)
  • Biotechnology (AREA)
  • Physics & Mathematics (AREA)
  • Analytical Chemistry (AREA)
  • General Physics & Mathematics (AREA)
  • Microbiology (AREA)
  • Toxicology (AREA)
  • Zoology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Peptides Or Proteins (AREA)
  • Medicines Containing Material From Animals Or Micro-Organisms (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
  • Preparation Of Compounds By Using Micro-Organisms (AREA)
US06/524,201 1982-08-20 1983-08-18 New protein PP13 extracted from human placental tissues and use thereof Expired - Lifetime US4500451A (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE3230996A DE3230996A1 (de) 1982-08-20 1982-08-20 Neues protein (pp(pfeil abwaerts)1(pfeil abwaerts)(pfeil abwaerts)3(pfeil abwaerts)), verfahren zu seiner anreicherung und gewinnung sowie seine verwendung
DE3230996 1982-08-20

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US (1) US4500451A (enrdf_load_stackoverflow)
EP (1) EP0101603B1 (enrdf_load_stackoverflow)
JP (1) JPS5959621A (enrdf_load_stackoverflow)
AT (1) ATE38521T1 (enrdf_load_stackoverflow)
AU (1) AU555699B2 (enrdf_load_stackoverflow)
CA (1) CA1213213A (enrdf_load_stackoverflow)
DE (2) DE3230996A1 (enrdf_load_stackoverflow)

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4592863A (en) * 1983-10-22 1986-06-03 Behringwerke Aktiengesellschaft Protein PP20, a process for obtaining it, and its use
US4599318A (en) * 1984-02-09 1986-07-08 Behringwerke Aktiengesellschaft Tissue protein PP19, a process for obtaining it, and its use
US4732891A (en) * 1985-09-30 1988-03-22 Kowa Co., Ltd. Placenta-derived anticoagulating substance, process for preparing same and anticoagulant comprising same as an effective component
US4748156A (en) * 1986-01-21 1988-05-31 Kowa Co., Ltd. Thrombin-binding substance and process for preparing the same
US5198366A (en) * 1986-03-23 1993-03-30 Technion Research & Development Foundation Ltd. Method for the detection of pregnancy disorders
WO2000058364A1 (en) * 1999-03-30 2000-10-05 Diagnostic Technologies Ltd. Antibodies to placental protein 13
US6271201B1 (en) 1993-07-15 2001-08-07 Board Of Regents, The University Of Texas System Methods for the selective regulation of placental prostanoids and inhibition of labor using IGF-I
US20030092188A1 (en) * 1998-01-29 2003-05-15 Diagnostic Technologies Ltd. Placental protein 13
US20060040337A1 (en) * 2002-08-29 2006-02-23 Hamutal Meiri Method of diagnosis of pregnancy-related complications

Families Citing this family (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE3418888A1 (de) * 1984-05-21 1985-11-21 Behringwerke Ag, 3550 Marburg Gewebeprotein pp(pfeil abwaerts)1(pfeil abwaerts)(pfeil abwaerts)8(pfeil abwaerts), verfahren zu seiner gewinnung sowie seine verwendung
ATE78342T1 (de) * 1987-03-24 1992-08-15 Technion Res & Dev Foundation Verfahren zur feststellung von schwangerschaftsstoerungen.
JP2898634B2 (ja) * 1987-03-24 1999-06-02 テクニオン リサ−チ アンド デイベロプメント フアウンデ−シヨン リミテイド 妊娠障害の測定方法
EP0302459A3 (en) * 1987-08-04 1990-02-07 Sumitomo Pharmaceuticals Company, Limited Human placenta-derived thermostable cell growth factor and a process for production thereof
WO2005101572A1 (en) 2004-03-31 2005-10-27 Ace Technology Multiband antenna using whip having independent power feeding in wireless telecommunication terminal

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4041021A (en) * 1972-04-29 1977-08-09 Behringwerke Aktiengesellschaft AP-glycoproteins and process for isolating them
US4254021A (en) * 1976-09-08 1981-03-03 Behringwerke Aktiengesellschaft Tissue specific protein and process for preparing same
US4348316A (en) * 1979-12-31 1982-09-07 Behringwerke Aktiengesellschaft New protein PP15, a process for its preparation and its use
US4368148A (en) * 1980-01-10 1983-01-11 Behringwerke Aktiengesellschaft Protein PP9, process for its enrichment and its isolation and its use

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2042430A (en) * 1934-06-18 1936-05-26 Lakeland Foundation Pregnancy antigen
DE2842467A1 (de) * 1978-09-29 1980-04-10 Behringwerke Ag Neues ubiquitaeres gewebsprotein pp tief 8
DE3228503A1 (de) * 1982-07-30 1984-02-02 Behringwerke Ag, 3550 Marburg Neues protein (pp(pfeil abwaerts)1(pfeil abwaerts)(pfeil abwaerts)7(pfeil abwaerts)), verfahren zu seiner anreicherung und gewinnung sowie seine verwendung

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4041021A (en) * 1972-04-29 1977-08-09 Behringwerke Aktiengesellschaft AP-glycoproteins and process for isolating them
US4254021A (en) * 1976-09-08 1981-03-03 Behringwerke Aktiengesellschaft Tissue specific protein and process for preparing same
US4348316A (en) * 1979-12-31 1982-09-07 Behringwerke Aktiengesellschaft New protein PP15, a process for its preparation and its use
US4368148A (en) * 1980-01-10 1983-01-11 Behringwerke Aktiengesellschaft Protein PP9, process for its enrichment and its isolation and its use

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
Bohn et al., Chemical Abstract, vol. 99, No. 508SH, 1983, "Purification and Characterization of Two New Soluble Placental Tissue Proteins PP13 and PP17 " Oncodevelopmental Biology and Medicine.
Bohn et al., Chemical Abstract, vol. 99, No. 508SH, 1983, Purification and Characterization of Two New Soluble Placental Tissue Proteins PP 13 and PP 17 Oncodevelopmental Biology and Medicine. *

Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4592863A (en) * 1983-10-22 1986-06-03 Behringwerke Aktiengesellschaft Protein PP20, a process for obtaining it, and its use
US4599318A (en) * 1984-02-09 1986-07-08 Behringwerke Aktiengesellschaft Tissue protein PP19, a process for obtaining it, and its use
US4732891A (en) * 1985-09-30 1988-03-22 Kowa Co., Ltd. Placenta-derived anticoagulating substance, process for preparing same and anticoagulant comprising same as an effective component
US4748156A (en) * 1986-01-21 1988-05-31 Kowa Co., Ltd. Thrombin-binding substance and process for preparing the same
US5198366A (en) * 1986-03-23 1993-03-30 Technion Research & Development Foundation Ltd. Method for the detection of pregnancy disorders
US6271201B1 (en) 1993-07-15 2001-08-07 Board Of Regents, The University Of Texas System Methods for the selective regulation of placental prostanoids and inhibition of labor using IGF-I
US6461613B2 (en) 1993-07-15 2002-10-08 Board Of Regents, The University Of Texas System Methods and compositions for the selective regulation of chorionic prostanoids
US20030092188A1 (en) * 1998-01-29 2003-05-15 Diagnostic Technologies Ltd. Placental protein 13
US7211405B2 (en) 1998-01-29 2007-05-01 Diagnostic Technologies Ltd. Placental protein 13
WO2000058364A1 (en) * 1999-03-30 2000-10-05 Diagnostic Technologies Ltd. Antibodies to placental protein 13
US6790625B1 (en) 1999-03-30 2004-09-14 Diagnostic Technologies Ltd. Antibodies to placental protein 13
US20060040337A1 (en) * 2002-08-29 2006-02-23 Hamutal Meiri Method of diagnosis of pregnancy-related complications
US7488585B2 (en) 2002-08-29 2009-02-10 Diagnostic Technologies Ltd. Method of diagnosis of pregnancy-related complications
US20090227036A1 (en) * 2002-08-29 2009-09-10 Diagnostic Technologies Ltd. Method of diagnosis of pregnancy-related complications

Also Published As

Publication number Publication date
DE3230996A1 (de) 1984-02-23
EP0101603A2 (de) 1984-02-29
DE3378414D1 (en) 1988-12-15
AU1816783A (en) 1984-02-23
EP0101603B1 (de) 1988-11-09
JPH0354680B2 (enrdf_load_stackoverflow) 1991-08-20
CA1213213A (en) 1986-10-28
JPS5959621A (ja) 1984-04-05
AU555699B2 (en) 1986-10-02
EP0101603A3 (en) 1986-05-28
ATE38521T1 (de) 1988-11-15

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